US2023032020A1PendingUtilityA1
Small-molecule covalent inhibition of ral gtpases
Est. expiryDec 19, 2039(~13.3 yrs left)· nominal 20-yr term from priority
A61K 31/357A61K 31/4412A61K 31/4433A61K 31/4184A61P 35/00A61K 45/06C07D 213/76A61K 31/4166A61K 31/44A61K 31/444G01N 2500/04A61K 31/5377A61K 31/4406G01N 2333/914A61K 31/18A61K 31/4965A61K 31/425
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Claims
Abstract
Disclosed herein are Ral-antagonist compounds that covalently bind to binding sites in RalA, and efficaciously inhibit Ral activity. The compounds include aryl sulfonyl fluoride compounds of the general structure of wherein X and Y are independently C or N, and R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo. These compounds expand Ral-inhibiting therapeutic options for treating Ral-driven cancers and one embodiment of the present disclosure is directed to the use of such compounds to treat cancer.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting a Ral GTPase said method comprising the step of contacting said Ral GTPase with a compound having the structure of
wherein
R 1 is H,
R 2 is H, C 1 -C 4 alkyl, or CF 3 ,
with the proviso that only one of R 1 or R 2 is
R 3 is H, —OCH 3 , —OCH 2 CH 3 , C 1 -C 4 alkyl, CH 2 (morpholino) or R 2 and R 3 together with the atom to which they are attached form a 5 to 6 membered cyclic, 5 to 6 membered heterocyclic, or 5 to 6 membered aryl ring, optionally forming a 1,4 dioxane, cyclohexane, morpholino, or piperazinyl ring;
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo;
R 5 is H or ═O;
R 6 and R 7 are independently halo;
X, Y and Z are independently C or N, optionally wherein Z is N and X and Y are each C, optionally wherein X is N and Y and Z are each C and optionally wherein X, Y and Z are each C.
2 . The method of claim 1 wherein
i) R 5 is H; and Z is C or
ii) R 5 is H; and Z is N.
3 . (canceled)
4 . The method of claim 1 wherein R 1 and R 2 are independently H or
with the proviso that one of R 1 or R 2 is H.
5 . The method of claim 1 wherein
i) R 1 is
R 3 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 ;
R 2 is H, or R 2 and R 3 together with the atom to which they are attached form a 1,4 dioxane or hexacyclic ring;
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , or —(SO 2 )CH 3 ;
R 6 and R 7 are independently halo or H, optionally wherein said halo is Cl or F; and
X and Y are independently C or N, optionally wherein X is N and Y is C, or
ii) R 1 is
R 2 is H;
R 3 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , or —OCH(CH 3 ) 2 ;
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo;
X and Y are independently C or N, optionally wherein X is N and Y is C or
iii) R 1 is
R 2 and R 3 together with the atom to which they are attached form a 1,4 dioxane or hexacyclic ring;
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , or —OH;
R 6 and R 7 are independently H or halo, optionally wherein said halo is F or Cl, optionally wherein R 6 and R 7 are each H, and
X and Y are independently C or N, optionally wherein X is N and Y is C, optionally wherein R 6 is H, X is N and Y is C, or
iv) R 1 is
R 2 is H, C 1 -C 4 alkyl, or CF 3 ;
R 3 is H or R 2 and R 3 together with the atom to which they are attached form a 6 membered heterocyclic, aryl ring, optionally a 1,4 dioxane, cyclohexane, morpholino, or piperazinyl ring;
R 4 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo;
X and Y are independently C or N, with the proviso that X and Y are not both N.
6 - 9 . (canceled)
10 . The method of claim 1 wherein said compound has the structure of:
wherein
X is N or C; and
R 4 is H, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo.
11 . The method of claim 1 comprising contacting a Ral GTPase with a compound selected from the group consisting of
12 . The method of claim 1 wherein said compound has the structure of:
wherein
X is N or C;
Z and J are independently O, N or C; and
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo.
13 . The method of claim 1 wherein said compound has the structure of:
wherein
X and Y are independently N or C;
R 3 is H, —OCH 3 , —OCH 2 CH 3 , C 1 -C 4 alkyl; and
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo.
14 . The method of claim 13 wherein said compound has the structure
wherein
X is N or C;
R 3 is H, or —OCH 3 ; and
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo.
15 . The method of claim 1 wherein said compound has the structure of:
wherein R 1 is H, —OCH 3 , —OCH 2 CH 3 , or —COCH 3 ; and
R 5 is H or R 1 and R 5 together with the atoms to which they are attached form a 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclic, or 5 to 6 membered aryl ring, optionally forming a 1,4 dioxane, cyclohexane, benzene, or piperazinyl ring.
16 . A pharmaceutical composition comprising a compound of a compound having the structure of
wherein
R 1 is H,
R 2 is H, C 1 -C 4 alkyl, or CF 3 ,
with the proviso that only one of R 1 or R 2 is
R 3 is H, —OCH 3 , —OCH 2 CH 3 , C 1 -C 4 alkyl, CH 2 (morpholino) or R 2 and R 3 together with the atom to which they are attached form a 5 to 6 membered cyclic, 5 to 6 membered heterocyclic, or 5 to 6 membered aryl ring, optionally forming a 1,4 dioxane, cyclohexane, morpholino, or piperazinyl ring;
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo;
R 5 is H or ═O;
R 6 and R 7 are independently halo;
X, Y and Z are independently C or N, optionally wherein Z is N and X and Y are each C, optionally wherein X is N and Y and Z are each C and optionally wherein X, Y and Z are each C.
17 . The pharmaceutical composition of claim 16 wherein
i) R 5 is H; and Z is C or
ii) R 5 is H; and Z is N.
18 . (canceled)
19 . The pharmaceutical composition of claim 16 wherein
R 1 and R 2 are independently H or
with the proviso that one of R 1 or R 2 is H.
20 . The pharmaceutical composition of claim 16 wherein
i) R 1 is
R 3 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 ;
R 2 is H, or R 2 and R 3 together with the atom to which they are attached form a 1,4 dioxane or hexacyclic ring;
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , or —(SO 2 )C 3 ;
R 6 and R 7 are independently halo or H, optionally wherein said halo is Cl or F; and
X and Y are independently C or N, optionally wherein X is N and Y is C, or
ii) R 1 is
R 2 is H;
R 3 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , or —OCH(CH 3 ) 2 ;
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo;
X and Y are independently C or N, optionally wherein X is N and Y is C or
iii) R 1 is
R 2 and R 3 together with the atom to which they are attached form a 1,4 dioxane or hexacyclic ring;
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , or —OH;
R 6 and R 7 are independently H or halo, optionally wherein said halo is F or Cl, optionally wherein R 6 and R 7 are each H, and
X and Y are independently C or N, optionally wherein X is N and Y is C, optionally wherein R 6 is H, X is N and Y is C or
iv) R 1 is
R 2 is H, C 1 -C 4 alkyl, or CF 3 ;
R 3 is H or R 2 and R 3 together with the atom to which they are attached form a 6 membered heterocyclic, aryl ring, optionally a 1,4 dioxane, cyclohexane, morpholino, or piperazinyl ring;
R 4 is H, C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo;
X and Y are independently C or N, with the proviso that X and Y are not both N.
21 - 24 . (canceled)
25 . The pharmaceutical composition of claim 16 wherein said compound is selected from the group consisting of
26 . The pharmaceutical composition of claim 16 wherein said compound has the structure of:
wherein
X is N or C;
Z and J are independently O, N or C; and
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo.
27 . The pharmaceutical composition of claim 16 wherein said compound has the structure of:
wherein
X and Y are independently N or C;
R 3 is H, —OCH 3 , —OCH 2 CH 3 , C 1 -C 4 alkyl; and
R 4 is C 1 -C 4 alkyl, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —(SO 2 )CH 3 , —OH, or halo.
28 . The pharmaceutical composition of claim 16 wherein said compound has the structure of:
wherein
X is N or C;
R 3 is H, or —OCH3; and
R 4 is —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OH, or halo.
29 . The composition of claim 16 wherein said compound has the structure of:
wherein R 1 is H, —OCH3, —OCH2CH3, or —COCH3; and
R 5 is H or R 1 and R 5 together with the atoms to which they are attached form a 5 to 6 membered cycloalkyl, 5 to 6 membered heterocyclic, or 5 to 6 membered aryl ring, optionally forming a 1,4 dioxane, cyclohexane, benzene, or piperazinyl ring.
30 . The composition of claim 16 further comprising a chemotherapeutic agent.
31 . A method of treating cancer said method comprising the step of administering a pharmaceutical compound of claim 16 .
32 - 39 . (canceled)Join the waitlist — get patent alerts
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